Field of the Invention
The present invention relates to novel compounds having neprilysin-inhibition activity. The invention also relates to pharmaceutical compositions comprising such compounds, processes and intermediates for preparing such compounds and methods of using such compounds to treat diseases such as hypertension, heart failure, pulmonary hypertension, and renal disease.
State of the Art
Neprilysin (neutral endopeptidase, EC 3.4.24.11) (NEP), is an endothelial membrane bound Zn2+ metallopeptidase found in many organs and tissues, including the brain, kidneys, lungs, gastrointestinal tract, heart, and the peripheral vasculature. NEP degrades and inactivates a number of endogenous peptides, such as enkephalins, circulating bradykinin, angiotensin peptides, and natriuretic peptides, the latter of which have several effects including, for example, vasodilation and natriuresis/diuresis, as well as inhibition of cardiac hypertrophy and ventricular fibrosis. Thus, NEP plays an important role in blood pressure homeostasis and cardiovascular health.
NEP inhibitors, such as thiorphan, candoxatril, and candoxatrilat, have been studied as potential therapeutics. Compounds that inhibit both NEP and angiotensin-I converting enzyme (ACE) are also known, and include omapatrilat, gempatrilat, and sampatrilat. Referred to as vasopeptidase inhibitors, this latter class of compounds is described in Robl et al. (1999) Exp. Opin. Ther. Patents 9(12): 1665-1677.
Ksander et al. (1995) J. Med. Chem. 38:1689-1700 describes dicarboxylic acid dipeptide NEP inhibitors of the formula:

CompoundRIC50 (nM)21g—C(O)—CH2—COOH9221a (R,S)—C(O)—(CH2)2—COOH521b (S,R)—C(O)—(CH2)2—COOH19021c (R,R)—C(O)—(CH2)2—COOH70021d (S,S)—C(O)—(CH2)2—COOH2721e—C(O)—(CH2)3—COOH9021f—C(O)—(CH2)4—COOH324Compound 21a, which has a succinic acid substituent, is the most active compound, with an IC50 of 5 nM. The authors observed that “the succininc acid in the P2′ site appears to be optimal since extension of the carboxylic acid chain by one (21e) and two (21f) methylene units decreased activity 18- and 65-fold.” The authors further noted that “decreasing the chain length by one methylene (21g) also showed an 18-fold decrease in activity.” (page 1692, 2nd column)